SZKOLENIE PODYPLOMOWE/POSTGRADUATE EDUCATION

Endokrynologia Polska/Polish Journal of Tom/Volume 62; Numer/Number 2/2011 ISSN 0423–104X

Gynecomastia — a difficult diagnostic problem Ginekomastia — trudny problem diagnostyczny

Marek Derkacz1, Iwona Chmiel-Perzyńska2, Andrzej Nowakowski1

1Department of Endocrinology, Medical University, Lublin, Poland 2Department of Family Medicine, Medical University, Lublin, Poland

Abstract is a benign, abnormal, growth of the male gland which can occur unilaterally or bilaterally, resulting from a prolife- ration of glandular, fibrous and . Gynecomastia is characterised by the presence of soft, 2–4 cm in diameter, usually discus- shaped enlargement of tissues under the . It is estimated that this pathology occurs in 32–65% of men over the age of 17. Gynecoma- stia is a psychosocial problem and may lead to a perceived lowering of quality of life. The main cause of gynecomastia is a loss of equilibrium between oestrogens and . Increased sensitivity for oestrogens of the breast gland, or local factors (e.g. an excessive synthesis of oestrogens in breast tissues or changes in oestrogen and receptors) may cause gynecomastia. Also, , thyroxine, cortisol, human chorionic gonadotropin, leptin and receptors for human chorionic gonadotropin, prolactin and localised in tissues of the male breast may participate in the etiopathogenesis of gyneco- mastia. Usually three types of gynecomastia are distinguished: physiological, idiopathic and pathological gynecomastia. The latter is the consequ- ence of relative or absolute excess of oestrogens. In this paper, frequent as well as casuistic causes of gynecomastia will be described. A diagnosis of gynecomastia is usually possible after a palpation examination. Ultrasonographic, mammographic or histopathological examinations are useful in aiding diagnosis. The five degree scale devised by Tanner and Marshall is useful in estimating disease progres- sion. (Pol J Endocrinol 2011; 62 (2): 190–201) Key words: gynecomastia, etiopathogenesis, diagnosis, psychosocial problem

Streszczenie Ginekomastia jest łagodnym, nieprawidłowym, występującym jedno lub obustronnie wzrostem objętości gruczołów piersiowych u męż- czyzn, wynikającym z rozrostu tkanki gruczołowej, włóknistej i tłuszczowej. Zmiany charakteryzują się obecnością miękkiego, zwykle dyskoidalnego powiększenia tkanek o średnicy 2–4 cm, zlokalizowanego pod brodawką sutkową. Szacuje się, że występuje u 32–65% mężczyzn powyżej 17. roku życia. Ginekomastia stanowi problem psychospołeczny i prowadzi do pogorszenia jakości życia mężczyzn. Główną przyczyną ginekomastii są zaburzenia równowagi pomiędzy estrogenami a androgenami. Do jej rozwoju może prowadzić rów- nież zwiększona wrażliwość tkanki gruczołu piersiowego na estrogeny i/lub czynniki miejscowe (takie jak np. nadmierna produkcja estrogenów w tkankach gruczołu piersiowego, a także zmiany dotyczące receptorów dla estrogenów i androgenów). Również prolakty- na, tyroksyna, kortyzol, ludzka gonadotropina kosmówkowa, leptyna oraz receptory dla b-hCG, prolaktyny i luteotropiny zlokalizowane w tkance męskich gruczołów sutkowych mogą brać udział w rozwoju ginekomastii. Wyróżnia się ginekomastię fizjologiczną, idiopatyczną i patologiczną, będącą wynikiem bezwzględnego lub względnego nadmiaru estro- genów. W pracy opisano zarówno częste, jak i kazuistyczne przyczyny ginekomastii. Rozpoznanie stawiane jest zwykle na podstawie badania palpacyjnego. W diagnostyce wykorzystywane są techniki obrazowe, takie jak ultrasonografia czy mammografia lub badanie histopatologiczne. W ocenie zaawansowania ginekomastii przydatna jest 5-stopniowa skala Tannera i Marshalla. (Endokrynol Pol 2011; 62 (2): 190–201) Słowa kluczowe: ginekomastia, przyczyny, diagnostyka, aspekty psychospołeczne

Introduction to four centimetres in diameter, located below the nip- ple. The enlargement of the glands is usually bilateral The term gynecomastia (Greek: gyne = woman, ma- and symmetrical; however, gynecomastia may also oc- stos = breast) was introduced in the first century A.D. cur unilaterally, usually on the left side [1]. The enlar- by Galen. Gynecomastia is marked by a benign, abnor- ged volume of the breast glands in some cases may be mal, unilateral or bilateral volumetric increase in men’s accompanied by tenderness and pain, the cause of breast glands as a result of the proliferation of glandu- which is usually the rapid growth of glandular tissue. lar, fibrous, and adipose tissue. Changes are characteri- Its occurrence among men over the age of 17 is estima- sed by a soft, usually discoidal tissue enlargement two ted at 32–65%. In some age groups, such changes may

 Marek Derkacz MD, Department of Endocrinology, Jaczewskiego 8, 20–954 Lublin, Poland, tel./fax: +48 81 724 46 68, e-mail: [email protected]

190 Endokrynologia Polska/Polish Journal of Endocrinology 2011; 62 (2) occur in up to 72% of men [2–4]. Diagnoses are often Table I. Gynecomastia — causes and frequency of their made on the basis of palpation exams: the diameter of occurrence [2] the palpable lesion should then exceed 2 cm. In dia- Tabela I. Ginekomastia — przyczyny i częstość ich wystę- gnosing gynecomastia, visual techniques such as ultra- powania [2] sonography or may prove useful. It may Cause Frequency also be diagnosed on the basis of a histopathology exam, of occurrence which necessitates invasive diagnostic methods [2]. In the assessment of gynecomastia, Tanner and Marshall’s Idiopathic 25% five-stage scale evaluating the proper development of Sexual maturity 25% the breast glands is useful [5]. Medications 10–20% Hepatic or poor nourishment 8% The causes of gynecomastia Primary 8% Orchidoncus 3% The commonest cause of gynecomastia is disturbance Secondary hypogonadism 2% of the balance between oestrogens (exhibiting a stimu- Hyperthyreosis 2% latory action on the breast gland) and androgens (which Kidney diseases 1% have an inhibitory function) [6–8]. The changes frequ- Others 6% ently occur in response to an increased production and/ /or activity of oestrogens and a decreased production and/or activity of . Increased sensitivity of Infancy the breast tissue to oestrogen may also lead to the de- Transient gynecomastia is observed in 60–90% of in- velopment of gynecomastia, at which time the deve- fants, being a result of the activity of maternal oestro- lopment of changes occurs despite the proper concen- gen found in the child’s organism. Changes usually give tration of these hormones in the blood. A major role in way to idiopathic regression within a few months. the pathogenesis of changes seems to be played by lo- cal factors, such as excessive production of oestrogens in the breast tissues, being a result of increased activity Gynecomastia as a result of excessive production of of , their decreased degradation, and also oestrogen and its precursors in relation to testosterone changes concerning oestrogen and androgen receptors is found in 20–70% of pubertal boys. The peak of symp- [9]. Likewise, prolactin (PRL), thyroxin, cortisol, human tom occurrence is experienced at 13–14 years of age. chorionic gonadotrophin (b-hCG), leptin, and receptors Changes usually give way to spontaneous regression for b-hCG, prolactin, and luteotropin localised in the in six months to three years. It seems that in the patho- tissue of men’s mammary glands may play a part in the genesis of gynecomastia, besides the upsetting of the development of gynecomastia [10–12]. hormonal balance, a major role may be played by an , once considered to be the elevated level of leptin, which has been observed in boys primary cause of gynecomastia, in fact plays a less si- with pubescent gynecomastia. This compound incre- gnificant role in its origination. In most patients with ases the activity of aromatase in the fatty tissue as well gynecomastia, the level of PRL in the blood is within as other tissues of the breast gland. This leads to a rise the normative range [12]. An elevated level of PRL may in the concentration of oestrogens and/or the oestrogen/ however inhibit the secretion of gonadotropins, evo- /androgen relation. The impact of leptin on the develop- king secondary hypogonadism, although gynecomastia ment of gynecomastia is also probably connected to its does not occur in all patients with hyperprolactinaemia. direct functional stimulation of the growth of mammary Enlargement of the breast glands is also affected by an gland cells or the increase of sensitivity of these cells to excess of (GH) and insulin-like growth oestrogen with concurrent functional activation of oestro- SZKOLENIE factor (IGF). The major impact of these substances on gen receptors in the breast gland tissue [14]. A signifi- PODYPLOMOWE the growth of breast gland size, and the increase of the cant overgrowth of glandular tissue persisting beyond proliferation index of the epithelium, have been demon- 17 years of age usually requires the application of the strated in experimental studies [13] (Table I). appropriate treatment. Cases of gynecomastia (often oc- curring unilaterally) are observed among adolescent boys Types of gynecomastia in the course of neurofibromatosis [15]. Physiological gynecomastia Physiological gynecomastia is most often defined as Senescence symptomless gynecomastia occurring in three periods About 30–85% of cases of physiological gynecomastia of life [3]: occur in men aged 50 to 80. The cause of the changes is

191 Gynecomastia — a difficult diagnostic problem Marek Derkacz et al.

most often a relative excess of oestrogens resulting from nection with SHBG, increase activity of aromatase, act an age-related reduced production of testosterone and anti-androgenously and increase PRL secretion [2, 17, intensification of its peripheral aromatisation to oestro- 22]. Enlargement of the breast glands among those tre- gen, which in turn leads to an upset of the androgen/ ated for arterial hypertension often testifies to the exi- /oestrogen balance. Gynecomastia occurring in the stence of a secondary cause of arterial hypertension or andropause period usually does not give way to idiopa- undesirable effects of applied hypertensive medications thic regression. Decreased range of testosterone levels, [23, 24]. Abuse of , marijuana, heroin and am- and in some cases an increased level of LH, occurs among phetamines also increases the risk of gynecomastia [25]. patients [16]. The fall in testosterone levels results from It may also be evoked by teratogenic substances acting a decreased efficiency of testicular hormones, and their on the foetus in the prenatal period, the effect of which intensified aromatisation connected with excessive ac- may cause subsequent hypogonadism in the foetus [26] cumulation of fatty tissues, being an important centre of (Tables II, III). aromatisation of androgens and oestrogens. As previously mentioned, the cause of gynecomastia is an imbalance between oestrogens and androgens. The Idiopathic gynecomastia upsetting of the oestrogen/androgen relation may also Idiopathic gynecomastia (of unknown origin) rivals result from both actual and relative excess of oestrogens. physiological gynecomastia as the most commonly dia- gnosed type of gynecomastia, and constitutes 25% of Gynecomastia in the course of all cases. Making such a diagnosis requires ruling out actual excess of oestrogens all other known causes of overgrowth of the breast glands. Proper concentrations of gonadotropin, sex Exogenous oestrogens, substances of oestrogenic hormones, and SHBG (sex-hormone-binding-globulin) and anti-androgenic function are often observed in patients [17]. However, according The common occurrence in a person’s environment of to Zgliczyński et al., increased concentrations of SHBG compounds of oestrogenic function carry with them the occur among men diagnosed with idiopathic gyneco- risk of development of gynecomastia. There are several mastia [18]. In response, clinical studies by Ernsos et al. categories of these substances, in the composition of confirm the existence of a correlation between idiopa- which are included compounds of weak oestrogen func- thic gynecomastia, , and decreased concentra- tion () capable of affecting a person’s he- tions of testosterone and LH, which may be a result of alth [55]. Among these, it is possible to distinguish diet increased conversion of testosterone into oestradiol in composition, such as meat and some fitoestrogen-conta- excessively developed fatty tissues [19]. It is assumed ining edible plants, which when consumed (long-term that impaired tissue response, which may be an effect and in large quantities) may increase the risk of the de- of a diminished number of androgen receptors, may velopment of gynecomastia [56]. Examples of fitoestro- also lead to the proliferation of glandular tissue in this gens are genistein contained in soy and other legumi- type of gynecomastia [20]. It seems that the develop- nous plants, and 8-prenylnaringenin contained in hops. mental basis of idiopathic gynecomastia may also lie in Martinez et al. described a case of gynecomastia as the a local increase in activity of aromatase [21]. result of high consumption of soy products [57]. Howe- ver, the effect of a diet rich in soy on the development of Pathological gynecomastia gynecomastia is not unambiguous. Experiments conduc- In the United States over the course of the last 50 years, ted on monkeys excluded the effect of a several-year- gynecomastia has been reported as an unwanted side- long soy-rich diet on the development of gynecomastia effect of more than 300 pharmaceutical drugs. Accor- [58, 59]. There were no demonstrated differences in the ding to various sources, drug-induced gynecomastia structure and mass of breast glands of individuals subsi-

SZKOLENIE constitutes 10–25% of all cases of gynecomastia [2, 22]. sting on a soy diet and a normal diet. Nor did the soy

PODYPLOMOWE It is often a consequence of chronic application of hor- diet have an effect on the concentration of oestradiol and monal drugs, antibiotics, preparations for the treatment testosterone in the serum of the animals studied in the of cardiovascular diseases, ulcers, chemotherapeutics, experiments. Histopathological and histomorphometric retroviral drugs and some psychiatric medications. The- studies on mammary glands have not demonstrated ir- se medications induce gynecomastia through various regularities or gynecomastic features [59]. mechanisms, mainly direct or indirect increasing of the Numbered among xenoestrogens are also synthetic oestrogen/androgen relation, the result of which is the compounds applied as additives to fodder. Moreover, disturbance of the activity of the hypothamalic-hypo- oestrogenic effects are displayed by substances applied physeal-nuclear axis. Therapeutic agents may also exert in agriculture such as plant-protecting agents. Compo- an oestrogenic effect, dislodge oestrogens from the con- unds of a weakly oestrogenic nature are also found in

192 Endokrynologia Polska/Polish Journal of Endocrinology 2011; 62 (2)

Table II. Selected drugs and substances capable of inducing gynecomastia on the basis of [2, 22, 27–54] Tabela II. Wybrane leki i substancje mogące wywoływać ginekomastię; na podstawie [2, 22, 27–54]

Antiandrogens/Androgen synthesis inhibitors , , , Antibiotics/Chemotherapeutics/Antifungal drugs/ Didanosine, , Ethionamide, , , /Anti-retroviral drugs , Stavudine, Zidovudine Drugs applied in the treatment of peptic ulcer disease , , Ranitidine Drugs applied in the treatment of cardiovascular diseases , , Captopril, Digitoxin, Diltiazem, Enalapril, , , Reserpine, , Hypolipidemic drugs Atorvastatin , Fenofibrate, Rosuvastatin Psychiatric drugs Diazepam, Phenothiazines, , SSRI (Fluoxetine, Paroxetine, Venlafaxine), Mirtazapine, , Tricyclic antidepressants Hormones Androgens and anabolic , Oestrogens and agonists of oestrogens, Chorionic gonadotrophin, Growth hormone Drugs applied in chemotherapy Vinca alkaloids (e.g. Vincristine, Vinblastine), Imatinib, Alkylating drugs, Methotrexate, Polychemotherapy Addictive drugs/Narcotics Alcohol, Amphetamine, Heroin, Marijuana, Others Auranofin, Buspirone, Dasatinib, Diethylpropion, , Etretinate, Phenytoin, Marinol, Metoclopramide, Penicillamine, Saquinavir, Sulindac, Theophylline

Table III. Mechanism of pharmacological action of selected drugs capable of inducing gynecomastia [17] Tabela III. Mechanizm działania farmakologicznego wybranych leków mogących wywoływać ginekomastię [17]

Drugs Mechanism of action

Diazepam, , Phenytoin, hCG, Clomiphene, Are metabolized to oestrogens, possess intrinsic oestrogenic activity Anabolic steroids, , Conjugated and synthetic or stimulate synthesis of oestrogens oestrogens Bicalutamide, Cimetidine, Flutamide, Isoniazid, Exhibit anti-androgenic properties or inhibit synthesis of androgens Ketoconazole, Cytotoxic drugs (Busulfan, Vincristine, Vinblastine), Marijuana, Methotrexate, Metronidazole, Omeprazole, Penicillamine, Ranitidine, Spironolactone Domperidone, Haloperidol, Metoclopramide, Induce hyperprolactinemia Phenothiazines Alcohol Increase metabolism and clearance of androgens Diazepam, Phenytoin Increase concentration of SHBG

industrial products, for example in paint and cleaning occurred as the result of the application of hygiene pre- products. An influence on a person’s hormonal mana- parations containing lavender oil and [62]. gement may also be exerted by pharmaceutical drugs, In vitro studies using isolated human cells such as contraceptive drugs and other hormonal medi- have confirmed the weakly oestrogenic and anti-andro- cations, of which a small amount makes its way into genic properties of these substances [62]. There have the water supply via the sewage system. also been cases of the development of gynecomastia in SZKOLENIE In literature there are described cases of the occur- the aftermath of consumption of nettle teas and Chine- PODYPLOMOWE rence of gynecomastia among prepubertal boys as se ‘Dong Quai’ tablets, popularly known as‘women’s a result of indirect exposure to preparations containing Ginseng’, and containing in their composition pulveri- oestrogens in their composition [60, 61]. In the blood of sed roots of Chinese Angelica (angelica sinensis) [63–65]. children whose mothers applied creams with oestro- The overgrowth of mammary glands among men has gen additives, Felner et al. revealed heightened levels been observed after the consumption of Burra Gokha- of oestradiol [60]. Edidin et al. also described a case of ru (tribulis terrestris), used by body-builders and athle- gynecomastia in a boy, of which the cause was the ap- tes as an alternative to steroids [66]. Brody et al. descri- plication of hair cream containing in its composition bed a case of an epidemic of gynecomastia among refu- substances of oestrogen function [61]. Similar cases have gees as a result of the application of specimens used in

193 Gynecomastia — a difficult diagnostic problem Marek Derkacz et al.

the treatment of lice infestation () which con- size and in roughly half of cases are accessible in palpa- tained in their composition , a compound tion exams of the abdominal cavity [78]. They are mar- with anti-androgenic properties [67]. ked by a tendency to secrete large amounts of substan- Taking into consideration the universal presence of ces such as , DHEA and DHEA sulpha- compounds in a person’s environment which may in- te (DHEA-S), being the precursor of oestrogens. Some of crease the risk of the development of gynecomastia, it these produce oestradiol and oestrone [2]. According to seems that precise determination of a person’s eating Bembo et al., there is an increased level of 17- habits and susceptibility to exogenous oestrogens/anti- detected in urine analysis in two thirds of those afflicted. androgens is called for. This especially pertains to tho- In some cases, there is an increased level of DHEA-S in se afflicted in whom all known causes of gynecomastia the serum [3]. According to Lanigan et al., gynecomastia have been ruled out. may sometimes be the sole symptom of the presence of a feminising tumour of the adrenal cortex [79]. Holiday gynecomastia In the early 1990s, Heufelder et al. described a case of gy- Gynecomastia in the course necomastia which appeared in a man after his return from of b-hCG-producing tumours a long vacation in the Virgin Islands. The authors of this Some of the tumours secreting b-hCG possess the ca- research, after excluding other known causes, recognised pacity for the uptake of oestrogen precursors and their that the cause of breast gland enlargement was a ‘vacatio- aromatisation to active oestrogens [3]. Human chorio- nary’ lifestyle, consisting of daily consumption of large nic gonadotrophin in its structure and function resem- amounts of alcohol and a significant intake of poultry con- bles LH. Increased levels of b-hCG stimulate Leydig cells taining in its composition oestrogens [68]. It seems that to secrete oestradiol. Mentioned among tumours pro- the risk of developing holiday gynecomastia may be par- ducing b-hCG are, among others, embryonic tumours ticularly increased by certain kinds of alcohol, for example of the , liver, and stomach [80]. There have also -containing bourbon [69]. Chronic alcohol been cases published of painful gynecomastia occurring consumption or occasional binge-drinking may lead to the among patients with clear cell renal cell carcinoma, lung impairment of testicular function, resulting in a decrease of neoplasms and b-hCG secreting tumours of the urina- testosterone production. Ethanol also inhibits the conver- ry tract. After surgical treatment, the levels of b-hCG sion of androgen precursors (androstenedione and dehy- diminished, reaching undetectable levels in standard droepiandrosterone- DHEA) into androgens in the liver. tests, and gynecomastia underwent regression [81–84]. Through a stimulatory effect on aromatase and adenylate cyclase, peripheral conversion of precursors of androgens Aromatase Excess Syndrome (AEXS) into oestrogens may also be intensified [70]. In turn, the in- Aromatase Excess Syndrome, also called familial gyne- hibitory effect on dopaminergic activity in the brain stimu- comastia, is a familial, genetic, heterogenic disease of lates PRL production in the pituitary gland. This may indu- autosomal dominant inheritance [85–87]. It is characte- ce the growth of breast gland tissue [71]. rised by an increased concentration of oestrogens in the In scientific literature as far back as the 1970s, cases blood serum, as a result of an augmentation of periphe- of consumption of poultry containing in its composi- ral conversion of C-19 androgens into oestrogens. tion , an oestrogen-like structure com- Probably the first documented occurrence of AEXS pound applied as a growth stimulator to animal fod- originates from the 14th century B.C. and was discove- der, have been described [72]. According to Dardick, red in the tomb of the Pharaoh Tutankhamun. This an additional factor which may increase the risk of ho- documentation confirms evidence of the occurrence of liday gynecomastia could be smoking large amounts of familial gynecomastia in the Pharaoh, his brother, fa- marijuana [73]. This seems to confirm the work of other ther and grandfather [88–90]. In 2005, Tiulpakov et al.

SZKOLENIE authors concerning the application of narcotics and their described a five-generational Russian family in which

PODYPLOMOWE effect on the breast gland [74, 75]. There are no reports the occurrence of gynecomastia was documented in excluding the effects of cannabis on the development of 16 family members. Symptoms of AEXS affected both gynecomastia among men [76]. As Heufelder et al. say, sexes and began developing in early childhood in the holiday gynecomastia syndrome should be taken into form of breast enlargement, rapid growth, and accele- consideration in every case of reversible gynecomastia rated bone age. In the case of the adults, the following prior to a diagnosis of idiopathic gynecomastia [77]. features were observed: short stature and gynecomastia among the men, and macromastia and more frequent Oestrogen-producing tumours of adrenal glands gynaecological diseases related to oestrogen excesses, Oestrogen-producing tumours of adrenal glands are such as cancer of the endometrium, uterus myomas or in most cases benign. They are characterised by their large the inflammation of menstruation, among the women

194 Endokrynologia Polska/Polish Journal of Endocrinology 2011; 62 (2)

[91]. The mutation causing the occurrence of AEXS has this therapy. The occurrence of side effects depends on not been defined. Presumably it may concern the P450 the mechanism of action of the administered substan- gene for aromatase [92]. The mutation causing the oc- ce. Among other drugs, anti-androgens currence of AEXS may reveal itself as early as in the which block androgenic receptors (bicalutamide, fluta- period of increased secretion of androgens of the adre- mide or ) are used in the treatment of pro- nal cortex in the time preceding sexual maturity, or also state cancer. In up to 90% of cases, these drugs may in its early stage [17, 93]. cause mild to moderate gynecomastia, in contrast to ste- roidal androgen-cyproterone, which has a significantly Gynecomastia in the course of 11b-hydroxylase lower occurrence of gynecomastic changes [104, 105]. Gy- and 21-hydroxylase deficiencies necomastia and are observed on average in There have been published cases of gynecomastia oc- 50% of men treated with bicalutamide and nilutamide (24– curring in boys caused by an increased peripheral co- –76% of patients respectively). Treatment with flutamide nversion of androstenedione, resulting from deficien- has been connected with occurrence of these symptoms cies of 11-b-hydroxylase (11-b-OHD) and 21-hydroxy- in 30–79% of patients [106]. However, treatment with one lase (21-OHD) [94,95]. In the case of 21-OHD deficien- LHRH agonist, leuprolide, induced gynecomastia and cy, there has been observed regression of symptoms as breast pain in only in 3–12.7% of cases [106]. a result of glucocorticoid replacement therapy. As Wa- śniewska et al. say, 21-OHD deficiency may be a more Gynecomastia after spinal cord injury frequently supposed cause of gynecomastia in both the Gynecomastia is a well-known medical phenomenon prepubertal and pubertal periods. The earliest possible among patients with spinal cord injuries [107, 108]. There- diagnosis is essential because prolonged gynecomastia fore it can be assumed that the disorders of the dience- is resistant to pharmaceutical treatment [95]. phalon play an important role in its etiology. Heruti et al. described several cases of the occurrence of gynecomastia Gynecomastia in the course of other genetic diseases after spinal cord injury. Enlargement of the breast glands The occurrence of gynecomastia is more frequent was observed one to six months after trauma. As the au- among men with karyotype 47, XXY (Klinefelter’s syn- thors say, diagnostics excluding gynecomastia should be drome) and among subjects with masculine phenoty- conducted in every patient after a spinal cord injury [108]. pe possessing karyotype 46, XX (MEN [Multiple endo- crine neoplasia] syndrome). According to Korenman, Stress-induced gynecomastia gynecomastia may accompany Klinefelter’s syndrome There are published cases of the occurrence of transient in approximately 80% of cases, and its primary cause is gynecomastia in response to stress. At the time of stress, primary hypogonadism [96]. Changes are accompanied increased concentrations of cortisol and oestradiol, with by elevated concentrations of LH and FSH, with con- an accompanying decrease in the level of testosterone current lowering of total and free testosterone and pro- in the blood serum, are observed, though the level of per levels of E2 and SHBG. Men with an additional X hormones was still found to be within the proper ran- chromosome are also marked by smaller gonad volu- ge. According to Gooren et al., the may me [97]. Klinefelter’s syndrome is accompanied by a 10- increase secretion of oestrogen precursors in response -20-foldincreased risk of the development of breast can- to stress, which among other things may be a cause of cer, something which is not found in cases of gynecoma- periodically occurring gynecomastia [109]. stia of other etiologies [96, 98]. Painful gynecomastia may also be one of the endocrinological complications in pa- Gynecomastia in the course tients suffering from myotonic dystrophy (Steinert’s of relative oestrogen excess disease) [99]. Occurrence of gynecomastia is also descri- Primary hypogonadism bed in the course of pseudomyopathic spinal muscular Primary hypogonadism is hormonal underactivity oc- SZKOLENIE atrophy [100]. Gynecomastia may also occur in persi- curring in the aftermath of testicular injury. Its cause PODYPLOMOWE stent Mullerian duct syndrome, a rare disease consisting may be genetic factors (e.g. Klinefelter’s syndrome) of, among other disturbances, the presence of fallopian often occurring in the course of testicular inflammation tubes, uterus or upper vaginal fragments among indi- (i.e. mumps), mechanical injuries, pharmaceutical tre- viduals of the male sex [101–103]. atment, chemo- or radiotherapy, and also in the course of serious diseases as well as overdose of stimulants. It Gynecomastia in the course of also occurs as an after-effect of surgical operations or The tolerance of hormonal therapy administered for poisoning, for example by heavy metals [2, 110–113]. prostate cancer is usually good. Gynecomastia or ten- Among patients with gynecomastia in the course of derness and pain of are potential side effects of primary hypogonadism, the presence of a -da-

195 Gynecomastia — a difficult diagnostic problem Marek Derkacz et al.

maging factor has been asserted in medical histories. In function return to normal, the effect of which may be physical examinations in some cases somatic features a so-called second [9]. resulting from lowered testosterone levels are present. In laboratory research, the lowering of total and free Gynecomastia in the course of testosterone levels in particular are asserted. A rise in Gynecomastia occurs commonly among patients suffe- the LH level stimulates aromatase in Leydig cells of the ring from alcohol-induced cirrhosis of the liver, often testicles to produce a large amount of oestrogens and associated with hypogonadism [117, 118]. Liver disease peripheral aromatisation of androgenic androstenedio- leads to the intensification of the peripheral process of ne to oestrogen does not give way to change. Gyneco- aromatisation of androgens to oestrogens. In some ca- mastia is also observed among castrated men [114, 115]. ses, heightened levels of SHBG are also claimed, which As Biglia et al. say, gynecomastia occurring among car- is a cause of reduction of free testosterone [9, 119]. Far- riers of the HIV virus tends to be induced by hypogo- thing et al. observed a significantly higher level of pro- nadism, and is not, as some researchers believe, a side- gesterone among men with non-alcohol-related cirrho- effect of retroviral therapy [116]. sis and gynecomastia compared to men without featu- res of overgrowth of the breast glands. No such depen- Secondary hypogonadism (hypothalamus-pituitary) dence was confirmed in the group of men with Gynecomastia may also be an effect of androgen deficien- alcohol-induced fatty degeneration of the liver or cirr- cy in the course of secondary hypogonadism, being a result hosis in the course of alcoholism [120]. of underactivity of the hypothalamus and/or pituitary gland. displays a synergistic effect with oestrogen on the mam- Because of a lack or decrease in secretion of pituitary gona- mary gland, stimulating growth of the glandular alve- dotropin, the testicles do not produce a proper amount of olus and the end-epidermis of canals. Among women, testosterone, and peripheral aromatisation of adrenal an- it appears with expression of receptors vital to lacta- drogens to oestrogens remains unperturbed and ensures tion. In the researched group, hyperprolactinaemia was normal oestrogen levels in the serum [3]. Secondary hypo- observed among 14% of those tested with liver disease; gonadism is characterised by low levels of gonadotropin however, this level did not correlate with the presence and testosterone. This form of hypogonadism is usually con- of gynecomastia [120]. In turn, as Van Thiel et al. sug- ditioned by organic illness of the hypothalamus or pitui- gest, alcoholics with a fatty liver and without features tary. The cause of hypogonadism may also be a genetic of gynecomastia are characterised by a decreased level defect, for example the disturbance of synthesis of gonado- of PRL and excessive response to TRH. In contrast, al- tropin with accompanying anosmia (Kallmann syndrome). coholics with both cirrhosis and gynecomastia are cha- Tumours and abscesses of the hypothalamus or pituitary racterised by an elevated level of PRL and a decreased gland, inflammation processes, skull injury, vascular chan- response to TRH [121]. There are also published cases ge, haemochromatosis and tuberculosis may also lead to of bilateral gynecomastia occurring in the course of pri- secondary hypogonadism. It may arise as a complication mary liver cancer (hepatocarcinoma) or in the form of from a surgical procedure, occur in the course of severe con- malignant hepatoma (fibrolamellar carcinoma) produ- stitutional illnesses, and also be a reaction to extreme overe- cing oestrogens. The symptoms of gynecomastia subsi- xertion. The cause of hypogonadism may also be rapid and ded after surgical removal of the tumours [122–124]. excessive reduction of body mass. All of these causes may be related to the risk of hypogonadism often accompany- Gynecomastia in the course of chronic ing gynecomastia. In the course of chronic kidney failure, gynecomastia Refeeding gynecomastia has been observed in around 18% of patients [125]. Men Gynecomastia occurring a few weeks after resumption with chronic kidney failure are marked by a number of

SZKOLENIE of a normal diet among persons extremely malnouri- hormonal disturbances including a low level of testo-

PODYPLOMOWE shed was observed for the first time among prisoners sterone in the blood serum, elevated levels of oestra- of war after World War II. The symptoms usually gave diol and LH, together with a slightly increased level of way to idiopathic regression after one or two years. The PRL in the blood serum. Hormonal disturbances often exact mechanism of inflammation was not recognised, regress after kidney transplantation, but dialysis does although Carlson suggests that it may be similar to that not affect them [126, 127]. Dialysis-related gynecoma- which occurs in gynecomastia in the period of sexual stia usually regresses idiopathically after one or two maturity [9]. Appreciable secondary to mal- years. The pathogenesis of change is similar to that oc- nourishment is often associated with hypogonadism curring in the course of refeeding gynecomastia. Prior to due to decreased gonadotropin secretion. Together with the initiation of dialysis, patients with kidney failure usu- body growth, secretion of gonadotropin and gonad ally have a low body mass resulting from the necessity

196 Endokrynologia Polska/Polish Journal of Endocrinology 2011; 62 (2) of adhering to a strict diet. In the course of dialysis, the level also stimulates synthesis of SHBG, which preferen- diet is expanded and patients usually gain weight [3]. tially binds testosterone leading to a decrease of the free testosterone level associated with normal or elevated free Gynecomastia in the course of oestradiol level. There are published cases of the regres- The occurrence of gynecomastia with an overactive thy- sion of bilateral gynecomastia and hormonal disturban- roid is estimated at around 10–40% [3]. Thyroid hor- ces (decreased gonadotropin level and decreased testo- mones increase synthesis of SHBG in the liver [77]. The sterone/oestradiol ratio) in groups of men after orchidec- effect of this is a rise in the concentration of total testo- tomy due to [138–140]. sterone, a lowered level of free testosterone and a rise The occurrence of gynecomastia has been observed in the concentration of oestradiol in the blood. The ef- in the course of testosterone treatment of men suffe- fect of weakly-bonded oestradiol with SHBG in those ring from hypogonadism. The reason for this type of suffering from hyperthyroidism is an elevated level of gynecomastia is peripheral conversion of testosterone free oestradiol alongside proper levels of testosterone to oestradiol through aromatase [141]. Gynecomastia in the blood serum. Hyperthyroidism also leads to in- may be also one of the reasons for withdrawing from creased peripheral conversion of androgens to oestro- hormone treatment. gens through aromatase [9]. Hyperthyroidism leads to Gynecomastia occurs in about 50% of body-builders the intensification of the adrenal process of steroidoge- who are long-term users of high doses of anabolic ste- nesis. A rise in production of androstenedione leads to roids [142]. increased peripheral synthesis of oestrone. After achie- ving a state of euthyroidism, there have been seen de- Other pathologies of the male mammary creases and even complete reversals of gynecomastic change and a subsidence of painful ailments [3, 128–130]. Changes of mastopathic character are described in ca- In some undiagnosed patients, gynecomastia may be ses of long-term diabetes type 1 which are estimated to the first symptom of an overactive thyroid [131] constitute less than 1% of mild illnesses of the mamma- ry. The pathogenesis of the changes is unknown, altho- Gynecomastia as a manifestation of testicular disease ugh the involvement of extracellular deposition of col- Castro-Magana et al. showed that varices of the sper- lagen, and inflammatory processes with the involve- matic cord may inflame the activity of dehydrogenase ment of B lymphocytes, have been suggested [143, 144]. 17b-hydroxysteroidal, thereby reducing the production of testosterone and leading to the development of gy- Diagnostics and differential diagnosis necomastia [132]. Gynecomastia may also be an endo- crinological manifestation of . Testicu- Establishing the cause of gynecomastia requires the lar cancer is among the commonest tumours occurring gathering of a patient’s complete medical history, the in men in their twenties and thirties. Each year, 3-6 new conduction of a thorough physical examination and cases are documented per 100,000 men. It is estimated precise assessment of the breast and testicular glands, that around 7–11% of men in the initial phase of the ill- and also of hormone levels such as: LH, FSH, PRL, te- ness develop gynecomastia which may precede the pre- stosterone, oestradiol, B-hCG and TSH. Assessment of sence of a palpation-detectable testicular lump and the liver and kidney function is also essential [10, 145]. Ul- occurrence of hormonal disturbances [133, 134]. In aro- trasonographic exams and core needle biopsy are also und 9% of patients, the development of gynecomastia is safe and effective methods of diagnosing cases of uni- preceded by the application of chemo- or radiotherapy lateral enlargement of the among men. in the treatment of testicular cancer [134]. In cases of Ley- According to Janes et al., the cause of about 93% of ca- dig cell tumours, where the cause of gynecomastia is in- ses of unilateral enlargement of the mammary gland creased concentration of oestradiol, the symptoms may among men is gynecomastia. The remaining cases are SZKOLENIE be present even in 20% of cases. Only 1-3% of all testicu- due to the occurrence of primary breast cancer, meta- PODYPLOMOWE lar tumours are Leydig cell tumours. Leydig cell tumo- stasis of lymphoma to the breast gland, and chronic in- urs can occur at any age, but most often concern boys flammation of the breast gland [146]. aged 5 to 10 and men aged 25 to 35. The presence of a tumour may be connected with gynecomastia and the Overgrowth of fat tissue lack of a palpation-detectable testicular lump, but noti- (pseudogynecomastia, false gynecomastia, ceable during ultrasonographic examination. About 90% lipomastia, steatomastia) of tumours are benign [126, 135–137]. Increased oestra- diol concentration inhibits LH secretion, resulting in In clinical practice, simple overgrowth of fat tissue lo- a decrease of testosterone level. An elevated oestradiol cated in the area of the is often mistaken for

197 Gynecomastia — a difficult diagnostic problem Marek Derkacz et al.

Table IV. Diagnostic assessment of gynecomastia according to Czajka and Zgliczyński [159] Tabela IV. Diagnostyczna ocena ginekomastii według Czajki i Zgliczyńskiego [159]

Relevant data from Physical examination Laboratory tests Visual examinations * medical history

— Duration of symptoms — Close examination of breasts — Total and free testosterone — USG of breasts or — Presence of pain/t — Close examination of testicles — LH, FSH, PRL mammography

/enderness (assessment of size and possible — TSH, fT4, — Ultrasonographic or pathological changes) — b-hCG thermographic examinations — Applied drugs/stimulants — Evaluation of abdominal cavity — DHEA-S or of testicles including possible changes in 17 ketosteroids in urine — CT of adrenal glands suprarenal glands and — Liver enzymes — MRI of pituitary gland enlargement of liver — — Presence of sexual — Thyroid gland examination dysfunctions and the presence of symptoms suggesting hyperthyroidism — Changes in body mass — Degree of virilisation — Presence of virilisation — Pilosity — Symptoms — Timbre of voice of hyperthyroidism — Musculature

*ordering of visual examinations should concern justified cases confirmed by clinical examination and laboratory tests

gynecomastia. Susceptible to pseudogynecomastia are cer among men is diagnosed in less than 5% of cases of obese persons as a result of rapid body mass reduction surgically removed changes concerning that gland [152]. [147]. A palpation exam is a useful means of differentia- The literature contains very rare cases of the occurren- ting between lipomastia and gynecomastia. In the case ce of ductal carcinoma among 15 and 16 year old boys of gynecomastia, after applying fingertip pressure on with unilateral gynecomastia [153, 154]. the nipple, glandular tissue is perceptible. In the case of An important role in visual diagnostics is played by obesity (and in healthy subjects), no resistance is felt, mammography and ultrasonography of the breast gland, with only the ribcage being detectable. Ultrasonogra- whose sensitivity in the case of cancer approaches 100%. phic exams of the mammary glands constitute a more Mammography, as opposed to ultrasonography, is mar- precise method of differentiation. ked by a somewhat greater specificity: about 90% compa- red to 74% in the case of USG [155]. In mammographic Breast cancer examinations, the presence of an irregular mass positio- ned under the lid of the nipple is most often observed, In contrast to other pathologies of the mammary glands, with unpronounced or ‘spike-like’ borders. The changes changes of a malignant nature must be taken into con- may be accompanied by calcification and gynecomastia. sideration with gynecomastia. Breast cancer, a rare di- In the regional assessment of lymph nodes, an important sease among men, mainly affects the elderly. The ill- role is played by ultrasonography [156]. With respect to ness occurs roughly125 times more commonly among the technical difficulties involved in conducting mammo- women than men. Breast cancer constitutes only 0.2% graphy on men, ultrasonographic examinations are recom- of all cancerous tumours in men and 0.5–1% of all cases mended as a method serving the evaluation of the patho- SZKOLENIE of cancer of that gland in both sexes [9, 148, 149]. A cen- logy of the mammary [157]. In distinguishing gynecoma- PODYPLOMOWE trally positioned, hard, painless, immovable lump is stia from breast cancer, alongside visual examinations often detected during palpation exams. The change is a very important role is played by the biopsy. In a case usually grounded in a base which consists of the when these methods do not allow for an unequivocal as- and/or breast muscle. In some cases it may also lead to sertion of benign change, the conducting of a mid-opera- deformity of the nipple and the so-called ‘orange peel’ tion biopsy should be considered [158]. symptom. In around one quarter of those afflicted, a bloody leakage from the nipple, which may be accom- Hyperprolactinaemia panied by ulceration, is seen [150]. Among the patients, lymphadenopathy is often observed occurring on the In differential diagnostics of gynecomastia, it is also tumorous side [151]. According to Krause, breast can- necessary to reflect on hyperprolactinaemia, which ac-

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